1. Field of the Invention
The present invention relates to novel compositions useful for arresting angiogenesis and membrane, cell or capillary leakage when used in effective amounts, and to methods of administering such compounds for purposes of arresting membrane leakage or capillary leakage, such as in abnormal angiogenesis, e.g., abnormal capillary growth.
2. Description of Background and Relevant Materials
Steroids generally have constituted a standard treatment when administered topically, percutaneously and intravenously by virtue of their anti-inflammatory effects.
Heparin and heparin fragments, when used alone have been reported to enhance tumor angiogenesis ("Angiogenesis Inhibition and Tumor Regression Caused by Heparin or a Heparin Fragment in the Presence of Cortisone", by Folkman et al. Science (1983) 221:719-725. The same article reports that angiogenesis can be inhibited by the combination of heparin and cortisone based upon animal tests. No human tests were conducted.
European Pat. No. 0 114 589, published Aug. 1, 1984, in the name of FOLKMAN et al., as well as the above article disclose a technique for the inhibition of angiogenesis in mammals by treatment with heparin and specific heparin fragments, in combination with a member selected from cortisone, hydrocortisone or the 11-alpha isomer of hydrocortisone so as to inhibit angiogenesis with subsequent regression of large tumor masses and alleged prevention of tumor metastasis in mammals.
In these materials engiogenesis is defined as the growth of new capillary blood vessels which is important in normal tissue growth such as the development of the embryo, formation of the corpus luteum and wound healing. It is also stated to be a component in pathologic processes such as chronic inflammation, certain immune responses and neoplasia. Angiogenesis is stated to be a property of most solid tumors and is necessary for their continued growth.
The patent application reports that heparin alone enhances the intensity of angiogenesis induced by tumors in vivo. Reference is made to work by SHUBIK et al. (J. Natl. Cancer Inst., Vol. 57, 769-774, [1976]) in which 6 alphamethyl-prednisolone partially suppressed tumor angiogenesis in hamster cheek pouch under certain conditions. Other publications have reported continued growth of tumors even in the presence of large doses of cortisone.
The application goes on to state that heparin fragments which are hexasaccharide or larger together with cortisone or hydrocortisone or the 11-alpha isomer of hydrocortisone will inhibit angiogenesis in mammals. The effect on angiogenesis is more definitively discussed in an article entitled: Toward a New Understanding of Vascular Proliferative Disease in Children, Pediatrics, Vol. 74, No. 5, November 1984.
The use of the purified form of heparin and heparin fragment in combination with certain steroid is also suggested by Crum et al., J. Cell Biology, October 1984, Abstract No. 581, page 158a.
The patent application is silent as to a key aspect of the mechanism behind angiogenesis, namely capillary exchange or leakage which Applicant alone has recognized to be the fundamental mechanism underlying angiogenesis.
In another approach, the use of sodium pentosan polysulfate SP.sub.54, as an alternative to heparin, in the treatment of interstitial cystitis is disclosed (Successful Treatment of Interstitial Cystitis with Sodium Pentosanpolysulfate, by C. Lowell Parsons et al., Journal of Urology. pp. 51-53, 1983). The authors indicate that SP.sub.54 is safe in humans, but mistakenly conclude that the method of action of the compound was through excretion in urine, and the relationship between the disease and its treatment to angiogenesis is not appreciated. This has now been found to be erronous because the fragment is destroyed in the kidney. The lower anticoagulant activity of the compound in comparison to heparin is also disclosed, see also Marsh, N. Gaffney, P. J.: The Effect of Pentosan Polysulfate (SP.sub.54) on the Fibrinolytic System of Man, IX Int. Congress on Thrombosis and Haemostasis, Stockholm, 1983.
The principles underlying the efficacy of particular steroids in arresting angiogenesis, in the presence of heparin fragments has been studied and reported by Crum et al., A New Class of Steroids Inhibits Angiogenesis in the presence of Heparin or a Heparin Fragment, Science, Vol. 230, 1375-1378, (1985). The article identifies the minimum essential structure of a steroid necessary to exhibit angiostatic properties. It is recognized that this steroid function is independent of glucocorticoid and mineralcorticoid activity.
Dimethyl sulfoxide, which also is used in the composition of the invention, has previously been known in the treatment of patients with intractible urinary frequency due to chronic prostatitis, chronic cystitis, tuberculous contracted bladder and interstitial cystitis (Okamura et al., Acta Urol. Japan, 31(4), 1985, 627-632; Fowler, J. E., Urol., 18(1), 1981, 21-26). Dimethyl sulfoxide (DMSO) which has been in use for many years has a number of interesting properties. Perhaps one of the most interesting and significant properties of DMSO is its ability to move other drugs through membranes. When mixed with DMSO many drugs appear to be potentiated in their physiologic effect. Thus, smaller drug dosages are required and less toxicity is demonstrated, WOOD et al., ANN.N.Y. Acad. Sci., 1975, vol. 243 (7-19). For this reason, investigations have been previously conducted on the use of dimethyl sulfoxide to increase the ability of chemicals to penetrate through the skin, a process which was reported to possibly contribute to tumor formation (Stenback, F. et al., A. N. Y. ACAD. Sci., 1975, vol. 243 (209-227). The same article studies the effects of adding other anti-inflammatory agents such as cortisone on tumorigenesis.
The inventor has previously reported the efficacy of dimethyl sulfoxide in the treatment of a specific type of interstitial cystitis--antibiotically induced--in combination with steroid and sodium bicarbonate buffer in a published Abstract, ANTIBIOTIC-INDUCED INTERSTITIAL CYSTITIS: AN AUTO-IMMUNE PHENOMENON, Abstract #108, published July 16, 1984, Abstract presented to American Urological Association, Western Section Meeting, Reno, Nevada; Antibiotic-Induced Interstitial Cystitis: A Model for Cell Membrane Instability, L. Gillespie, et al., Amer. Urological Association, Journal of Urology, 80th Annual Meeting of the AUA in Atlanta, Ga., Apr. 10, 1985. These reports, however, were silent as to the use of pentosan polysulfate, and angiogenesis was never specifically mentioned.